N-(pyridyl)-N{40 -alkyl-N{40 -(2-alkoxycarbonylbenzenesulfonyl)-glycineamides and derivatives

ABSTRACT

A process for the synthesis of N-aryl-3,4-dihydro-2-alkyl-4-oxo2H-1,2-benzothiazine-3-carboxamide 1,1-dioxides by treatment of N-aryl-N&#39;&#39;-alkyl-N&#39;&#39;-(2&#39;&#39;alkoxycarbonylbenzenesulfonyl)glycineamides, useful intermediates for said process, with an alkali or alkaline earth metal hydride in a reaction-inert solvent at 50*-150* C., said products being antiinflammatory agents.

United States Patent [191 Lombardino Dec. 16, 1975 N-(PYRIDYL)-N-ALKYL-N'-(2- ALKOXYCARBONYLBENZENESUL- FONYL)-GLYCINEAMIDES AND DERIVATIVES Joseph G. Lombardino, Niantic, Conn.

Assignee: Pfizer Inc., New York, NY.

Filed: Apr. 19, 1974 Appl. No.: 462,212

Related US. Application Data Division of Ser. No. 353,607, April 23, 1973, Pat. No. 3,853,862.

Inventor:

U.S. Cl.260/294.8 F; 260/306.8 R; 260/307 H;

260/559 A; 260/561 A; 260/470; 260/243 R; 424/263; 424/270; 424/272 Int. Cl. C07D 213/56 Field of Search 260/294.8 F

[56] References Cited UNITED STATES PATENTS 7/1971 Lombardino 260/243 Primary ExaminerAlan L. Rotman Attorney, Agent, or FirmConnolly and Hutz [57] ABSTRACT 4 Claims, N0 Drawings N-( PYRIDYL )-N -ALKYL-N-( Z -ALKOXYCAR- BONYLBENZENESULFONYL )-GLYCINEAMIDES AND DERIVATIVES This application is a division of application Ser. No. 353,607, filed Apr. 23, 1973 and now US. Pat. NO. 3,853,862.

BACKGROUND OF THE INVENTION This invention relates to a process for the synthesis of l,2-benzothiazine-3-carboxamides, and in particular to the preparation of N-aryl-3,4-dihydro-2-alkyl-4-oxo- 2H- 1 ,2-benzothiazine l 3-carboxamide 1 ,l-dioxides, a class of compounds useful as antiinflammatory agents, and to N-aryl-N'-alkyl-N-(2'-alkoxycarbonylbenzenesulfonyl )glycineamides as useful intermediates for said process.

Synthesis of 3,4-dihydro-2-alkyl-4-oxo-2H-l,2-benzothiazine-3-carboxamide 1,1-dioxides has been previously achieved by amination of the corresponding 3- carboxylic acid ester or by treatment of the parent 3,4-dihydro-2-alkyl-4-oxo-2H- 1 ,2-benzothiazine 1,1- dioxide with the appropriate isocyanate, Lombardino, et al., J. Med. Chem, 14, N71 (1971) and Zinnes, et al., ibid., 16, 43 (1973) and US. Pat. No. 3,591,584. In addition, Zinnes, et al., 100. cit., has taught the preparation of 3-carboxamides by treatment of the pyrrolidine enamine of 3 ,4-dihydro-2-methyl-4-oxo-2H- l ,2-benzothiazine, l,l-dioxide with phosgene followed by treatment of the resulting 3carbonyl chloride with an appropriate amine.

US. Pat. No. 3,714,155 discloses 4-hydroxy-2,N- dimethyl-2I-I-1 ,2-benzothiazine-3-carboxanilide, 1,1- dioxides as antiinflammatory agents, synthesized by methylation of the corresponding N-phenyl carboxamide with dimethylsulfate in the presence of sodium hydride.

SUMMARY OF THE INVENTION It has now been discovered that preparation of compounds of the formula wherein R is selected from the group consisting of phenyl; monosubstituted phenyl wherein said substituent is fluoro, chloro, methyl or methoxy; 2-thiazolyl; 4,5-dimethyl-2-thiazolyl; Z-pyridyl; 6-methyl-2-pyridyl; and -methyl-3-isoxazolyl; R is alkyl containing one to three carbon atoms; and X is a substituent selected from the group consisting of hydrogen, methyl, methoxy, fluoro, chloro and bromo, which comprises contacting a compound of the formula:

co R

so irca comm wherein R is alkyl containing from 1 to 3 carbon atoms, with an alkali or alkaline earth metal hydride in a reaction-inert solvent at 50l50 C. leads to the desired compounds which are potent nonsteroidal antiinflammatory agents.

Also claimed, as useful intermediates leading to the final products, are compounds of the formula CO R SO IiICH CONHR wherein R is selected from the group consisting of phenyl; monsubstituted phenyl wherein said substituent is fluoro, chloro, methyl or methoxy; Z-thiazolyl; 4,5- dimethyl- 2-thiazolyl; 2-pyridyl; 6-methyl-2-pyridyl; and 5-methyl-3-isoxazolyl; R is alkyl containing one to three carbon atoms; and X is a substituent selected from the group consisting of hydrogen, methyl, methoxy, fluoro, chloro and bromo.

Also considered within the scope of the instant invention is the process wherein R is alkyl of up to 8 carbon atoms, aryl or aralkyl, and wherein the metal hydride is replaced by a suitable organometallic reagent.

A preferred feature of the process leading to the compounds of the present invention is the use of sodium hydride as the metal hydride and tetrhydrofuran V as the reaction-inert solvent, while the preferred intermediates are N-(aryl)-N'-methyl-N-(2'-alkoxycarbonylbenzenesulfonyl )glycineamides.

DETAILED DESCRIPTION OF THE INVENTION A The aforementioned reaction is depicted in the following scheme CO R metaI X hydrlde SO IiICI-I CONHR -R OH 0 l X T N/ CONl-IR wherein R R R and X are as previously described.

In the above reaction of the benzenesulfonylglycineamide with a metal hydride the ratio of reactants is two equivalents of hydride per mole of glycineamide. In practice, a slight excess of 5-10% over two equivalents of the metal hydride has no deleterious effect on the formation of the desired product.

It is also desirable to conduct said reaction in a reaction-inert solvent. By such a solvent, or mixtures thereof, is contemplated those, which under the conditions of the instant process, do not enter into appreciable reactionwith either the starting reagents or products. It is preferred that non-aqueous. aprotic, polar solvents be employed. Suitable solvents or mixtures thereof which are included in this group are alicyclic ethers, di(lower)-alkoxyalkanes, di(lower)alkylsulfoxides, di(lower)alkyl(lower)alkanoic amides and hexa(- lower)alkylphosphoramides. Favored solvents for the present process invention are tetrahydrofuran, dioxane, dimethylformamide and dimethylsulfoxide The especially preferred solvent is tetrahydrofuran.

It is also preferred, although not a requirement, that the employed solvent be water-miscible.

Reaction time is not critical and is inherently dependent on concentration, reaction temperature and reactivity of the starting materials. In general, when temperatures of 50l00 C. are employed, the reaction time will vary between 4-10 hours.

Regarding temperature range, it is preferred, for practical reasons, that the instantly claimed process be heated in order to obtain optimum yields of the desired products. A temperature range of 501 50 C. is operative, with a preferred range of 50l00 C.

At the conclusion of the cyclization reaction the mixture is cooled and added to water, to which is then added sufficient acid to render the mixture acidic to litmus paper. The product is then extracted with a water-immiscible solvent, such as methylene chloride or chloroform, and the organic extracts concentrated to dryness. Further purification of the products is effected by recrystallization from an appropriate solvent.

The intermediate which are cyclized under the conditions of the present process, are prepared as shown by the following flow diagram:

2 2 Cll OCONCH CO H 1 I EEDQ QlCH OCON'CH CONHR 2 2 2 R NH Z i 2 l R NCH CONHR co R co R (3)+xI 23 23 2 SO NCH CONHR ll-Ethoxycarbonyl-2-ethoxy- 1,2-dihydroquinoline The glycine derivatives (1) are readily prepared by the methods reviewed by Greenstein and Winitz, Chemistry of the Amino Acids, John Wiley & Sons, Inc.. New York, NY. 1961, Volumes 1-3.

As previously mentioned, the compounds of the present process invention are useful as antiinflammatory agents, and US. Pat. No. 3,591,584 teaches how to use these compounds for this utility. Of particular interest in the present invention are the synthesis of benzothiazine l.l-dioxide wherein R is methyl, X is hydrogen and R is phenyl, Z-pryidyl. 2-thiazolyl or 6-methyl-2- pyridyl.

benzenesulfonylglycineamides,

The particularly preferred benzenesulfonylglycineamide' intermediates are those wherein R, is phenyl, pyridyl, 2-thiazolyl or 6-methyl-2-pyridyl and R and R are each methyl.

The examples which follow are given by way of illustration, and are not to be construed as limitations of this ivention, many variations of which are possible within the scope and spirit thereof.

EXAMPLE 1 N-(2-Thiazolyl)-3,4-dihydro-2-methyl-4-oxo-2H-1,2- benzothiazine-3-carboxamide l 1 -dioxide To 25 mg. (0.068 m mole) of N-(2-thiazolyl)-N'- methyl-N 2 '-methoxycarbonylbenzenesulfonyl glyci'neamide in 2 ml. of dry tetrahydrofuran maintained under a nitrogen atmosphere is added 6.5 mg (0.135 m mole) of a 50% sodium hydride suspension in oil, and the resulting reaction mixture heated under reflux overnight. The reaction mixture comprised of a yellow suspension is quenched with ice and subsequently acidified with 3N hydrochloric acid. The product is extracted with chloroform and the extracts combined and dried over sodium sulfate. The drying agent is filtered and the filtrate concentrated to a gum, which on trituration with 0.5 ml. of chloroform and 3 ml. of hexane yields 3.3 mg. of the desired product, m.p. l72193 C. Recrystallization, m.p. 256 C. dec., provides material identical to that prepared in US. Pat. No. 3,591,584.

EXAMPLE 2 3,4-Dihydro-2-methyl-4-oxo-2H- l ,2-benzothiazinecarboxanilide l l-dioxide To a solution of 3.77 g. (0.01 mole) of N-phenyl-N- methyl-N 2-ethoxycarbonylbenzenesulfonyl glycineamide in 40 ml. of dimethylformamide maintained under a nitrogen atmosphere is added portionwise 960 mg. (0.02 mole) of a 50% sodium hydride suspension in oil, and the reaction mixture heated at steam bath temperatures for 6 hrs. The mixture is cooled, poured into ice and water and acidified with 6N hydrochloric acid. The product is extracted with chloroform and the combined chloroform extracts (3) are back-washed with water and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue gum induced to crystallize by trituration with cold isopropanol. The filtered product proves to be identical with that reported in US. Pat. No. 3,59 l ,5 84.

EXAMPLE 3 N-( 6-Methyl-2-pyridyl )-3,4-dihydro-2-methyl-4-oxo- 21-1-1 ,2-benzothiazine-3carboxamide l l-dioxide In a manner similar to Examples 1 and 2, 2.03 g. (5 m moles) of N-(6-methyl-2-pyridyl)-N-methyl-N'-( 2- propoxycarbonylbenzenesulfonyl)glycineamide in 25 ml. of dioxane is treated with 205 mg. (5 m moles) of calcium hydride and the resulting mixture heated under reflux overnight. The cooled reaction mixture is quenched in ice, acidified, and the product extracted with methylene chloride. The organic extracts are combined, dried over sodium sulfate and concentrated in vacuo to a gum. Trituration with cold acetonitri followed by filtration provides the desired product.

EXAMPLE 4 oxide, to yield the desired crude product. Further purification is achieved by recrystallization from acetic acid.

EXAMPLE 5 The procedure of Examplel is again repeated. Starting with the appropriate N-aryl-N-alkyl-N-alkyl-N- (2-methoxycarbonylbenzenesulfonyl )glycineamides to provide the following congeners:

EXAMPLE 6 Starting with the requisite N-aryl-N-alkyl-N-(2- methoxycarbonylbenzenesulfonyl)glycineamide and the indicated metal hydride, the procedure of Example 2 is repeated wherein the following compounds are synthesized (product, metal hydride):

3 -methyl-3,4-dihydro-2-methyl-4-oxo-2H- 1 ,Z-benzothiazine-3-carboxanilide 1,1-dioxide, LiH; 4-methoxy-3 ,4-dihydro-2-ethyl-4-oxo-2I-I-1 ,Z-benzothiazine-3-carboxanilide 1,1-dioxide, Cal-I 4-chloro-3,4- dihydro-2-ethyl-4-oxo-2H-1 ,2-benzothiazine-3-carboxanilide 1,1-dioxide, KH; N-(6methyl2-pyridyl)-3,4- dihydro-Z-n-propyl-4-oxo-2H- 1 ,2-benzothiazine-3-carboxamide 1,1-dioxide, Nal-l; 2-fluoro-3.4-dihydro-2- methyl-4-oxo-2H-1 ,2-benzothiazine-3-carboxanilide 1.1-dioxide, RbH; 4'-fluoro-3,4-dihydro-2-ethyl-4-oxo- 21-1-1 ,2-benzothiazine-3-carboxani1ide l l -dioxide,

Cal-l N-( Z-thiazolyl )-3,4-dihydro-2-i-propyl-4-oxo- 2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, Csl-l; N-( 4,5-dimethyl-2-thiazolyl )-3 ,4-dihydro-2- methyl-4-oxo-2H- l ,2-benzothiazine-3-carboxamide l ,1-dioxide,BaH- N-( Z-furyl )-3 .4-dihydro-2-methyl-4- oxo-2H-1 ,Z-benzothiazine-3-carboxamide 1 l-dioxide, Cal-l N-(Z-furyl)-3,4-dihydro-2-methyl-4-oxo-2H-1 ,2- benzothiazine-3 -carboxanilide 1,1-dioxide, KH: 2'- chloro-3,4-dihydro-2-ethyl-4-oxo-2l-l-1,Z-benzothiazine-3-carboxanilide 1,1-dioxide, MgH N-(2-pyridyl)- 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3- carboxamido 1,1-dioxide, RbH; N-(6-methyl-2- pyridyl)-3,4-dihydro-2-ethyl-4-oxo-2H-1 .2-benzothiazine-3-carboxamide 1,1-dioxide, LiH; 4'-methyl-3,4- dihydro-Z-methy-4-oxo-2H-1,2-benzothiazine-3-carboxanilide 1,1-dioxide, KH; N-(2-thiazolyl)-3,4-dihydro-2-i-propyl-4-oxo-2H-1 ,2-benzothiazine-3-carboxamide 1,1-dioxide, BaH N-(5-rnethyl-3-isoxazolyl)- 3 ,4-dihydro-2-methyl-4-oxo-2H- 1 ,2-benzothiazine-3- carboxamide 1,1-dioxide. CaH- and N-(5-methyl-3- isoxazolyl)-3,4-dihydro-2-methyl-4-oxo-2l-l-1,2-benzothiazine-3-carboxamide 1,1-dioxide, LiH.

PREPARATION A Benzyloxycarbonylglycineamides 1 N-Methyl-N-benzyloxycarbonyl-N-( Z-thiazolyl glycineamide (2: R 2-C H NS; R CH R CH To a yellow solution of 9.44 g. (42.3 m moles) of commercially available N-benzyloxycarbonyl-N- methylglycine and 4.8 g. (48 m moles) of 2-aminothiazole in ml. of dry tetrahydrofuran under a nitrogen atmosphere is added dropwise 13 g. (53 m moles) of N-ethoxycarbonyl-Z-ethoxy-1,2-dihydro-quindine in 75 ml. of the same solvent. The resulting reaction mixture is allowed to stir at room temperature for 1 hr. and is then heated under reflux for 2 hrs. The solution is cooled in ice and the resulting solids filtered and dried, 4.6 g.. m.p. 203205 C.

Anal. Calcd for C H, O N S: C. 55.06; H, 4.59; N, 13.76. Found: C, 55.02; H, 4.94; N, 13.71.

2. In a similar manner to Preparation A-l, starting with the requisite glycine derivative and aryl amine, the following benzyloxycarbonylglycineamides are synthesized as intermediates:

PREPARATION B Glycineamides l. N-Methyl-N-(2-thiazolyl)glycineamide (3: R,

CH3; R2

To 5 g. of N'-methyl-N-benzyloxycarbonyl-N-(2- thiazolyl)glycineamide under a nitrogen atmosphere is added slowly with stirring 50 ml. of -a 33% hydrogen bromide solution in acetic acid. After the vigorous evolution of carbon dioxide has subsided, the reaction mixture is allowed to stir at room temperature overnight. Diethyl ether (275 ml.) is added and the precipitated solids filtered and dried, 5.4 g., m.p. 242-244 C., dec.

The analytical sample is recrystallized from ethanoldiethyl ether.

Anal. Calcd for C H ON S. 2HBr: C, 21.64; H, 3.33; N, 12.62. Found: C, 22.36; H, 3.34; N, 12.87.

The free base is generated by treatment of an aqueous solution of the hydrobromide salt with an aqueous sodium hydroxide solution, followed by extraction of the free base into a water-immiscible solvent such as benzene.

2. N-Alkyl-N-Arylglycineamides Starting with the requisite intermediate from Preparation A-2 and following the procedure of Preparation 8-1, the following intermediate products are prepared:

R. .NHCH,CoNHR,

PREPARATION C Z-Carboalkoxybenzenesulfonyl Chlorides resulting pale yellow solution is stirred for 30 min. at.

O5 C. and is filtered through a sentered glass filter.

The above filtrate containing the diazonium salt is slowly added dropwise to a solution resulting the addition of a cold solution of 40 g. of sulfur dioxide in 200 ml. of glacial acetic acid to a'cold suspension of 8 gv of cupric chloride in l 1 1 ml. of glacialacetic acid. During the second half of the addition and for 20min. after the addition is Complete, gas evolution is evident. After stirring the reaction mixture for 1 hr. in the cold, 1.4 l. of ice water is added and the precipitateintermediate product is filtered and dried in vacuo, 9.2 g., m.p. 6062 C.

Meerewein, et al., Chem. Ber., 90, 841 (1957) reports a m.p. of 64-65 C. for this compound which is prepared by a similar procedure.

2. Substituted Z-Carboalkoxybenzenesulfonyl chlorides Starting with the appropriately substituted anthranilic acid esters which are either known in the chemical literature or readily prepared by methods known to those skilled in the art and employing the procedure of Meerwein, et al. or that of Preparation C-l, the following sulfonyl chlorides are synthesized:

PREPARATION D N-Benzenesulfonylglycineamides l. N-(2-Thiazolyl)-N -methyl-N'-(2 -methoxyca rbonylbenzenesulfonyl)glycineamide N'-Methyl-N-( Z-thiazolyl )glycineamide, generated from 4.84 g. of the corresponding dihydrobromide salt, in 50 ml. of benzene is treated with 3.41 g. of 2- methoxycarbonylbenzenesulfonyl chloride, and the resulting mixture heated under reflux for 30 hrs. The reaction mixture is cooled and the precipitated solids filtered, washed with benzene and partitioned between water and chloroform. The water layer is extracted several additional times with chloroform, and the chlocominued roform extracts combined and dried over sodium sulx R. R: R fate. The organic solvent is removed in vacuo and the CHIO 2 ClC"H4 CHI, CH,l tan residual solid is triturated with hexane and filtered, 4-CH,, O 2C,H;,O CH CH; 640 mg, mp. 215 C. dec. The analytical sample is 5 gf g-g QEflfg SE 3 2 I 7 recrystallized from methanol, m.p. 216-218 C. dec. 5 cH,,o 2 C,H,N- C. ,H, CH Anal. Calcd for C I-1 0 19 8 c, 45.52; H, 4.09; N, 2 53 8 g:g%m g; 53 11.37. Found: C, 45.02; H, 4.12; N, 11.71. 6 CH,,o C.,H, CH" 6CH;,O C.,H5 C2H.-, CH1, 2 l O 6-CH;,0 4-CH,,oC.,H,- EH1, 8:1, 6CH;O -4ClC-H H. N-Aryl-N -alkyl-( 2 -alkox ycarbonylbenzenesulfonyl H 3-CH:C,;l-l CH; CH; g'ycineamides zin amm 1, 1] 3 3 Starting with the requisite intermediates from Prepaf'gg g:"g":8

1! 2| I rations B and C and employing the procedure of Prepa- H 5 CH,, 3 C,,HNo- CH;, CH, ration D-l the following intermediates are prepared: 15 a 2"g g C H N E a UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3, 927, 002 DATED December 16, 1975 INVENTOMS) 2 Joseph G. Lombardino It is certified that error appears in the ab0ve-identified patent and that said Letters Patent are hereby corrected as shown below:

Col. 6, line 26, "benzothiazine-3 carboxanilide" should read benzothiazine-3-carboxamide 1,1-dioxide, LiH;

3 -methoxy3 4dihydr0-2- pr0py1-40X02Hl Z-benzothiazine-3- cairboxanilide Signed and Scaled this sixth Day of April/976 [SEAL] A nest:

RUTH C. MASON ,4 Hurling ()I/irtr C. MARSHALL DANN ('nmmissinm'r nj'lau'nrs uml Trmlcmurkx 

1. A COMPOUND OF THE FORMULA
 2. A compound of claim 1 wherein X is hydrogen and R2 and R3 are each methyl.
 3. The compound of claim 2 wherein R1 is 2-pyridyl.
 4. The compound of claim 2 wherein R1 is 6-methyl-2-pyridyl. 